Proteins secreted by the heart are called cardiokines. After secretion, cardiokines, such as cytokines, growth promoters and stem cell homing factors affect ischemic damage, as well as stem cell survival and engraftment. But ischemia impairs protein folding and secretion, and negatively impacts stem cell-mediated regeneration. However, we discovered a secretion process that resists this inhibition, enabling the release of certain beneficial cardiokines, just when they are needed the most. The objectives of this study are to examine the functions of, and molecular mechanisms governing this secretion process in cardiac myocytes, in vitro and in vivo, and in cardiac stem cells. We discovered this process while studying the beneficial cardiokine, mesencephalic astrocyte-derived neurotrophic factor (MANF), which resides in the endoplasmic/sarcomplasmic reticulum (ER/SR). Our hypothesis is that 1) GRP78 regulates the secretion of beneficial ER stress cardiokines from cardiac myocytes and cardiac progenitor cells by mediating the conditional retention of proteins in the ER/SR, and 2) CPCs are specially configured with a novel cytosolic form of GRP78 that enhances survival, as well as cardiokine secretion during ER stress.We will address this hypothesis by using MANF as a model cardiokine, GRP78 gain- and loss-of-function, cultured cells and mouse hearts, /\AV9-mediated in vivo gene transfer, and zero-distance live cell cross linking in the following specific aims: 1- to determine the mechanism by which GRP78 regulates cardiokine secretion from cardiac myocytes, 2- to assess GRP78-regulated cardiokine secretion in the heart, in vivo, and determine the effects of disrupting this secretion on ischemic damage and regeneration, and 3- to examine the effects of GRP78 in the ER, as well as a novel, cytosolic form of GRP78 on cardiokine secretion, responses to ER stress and survival of cardiac stem cells. The results of these studies will facilitate the design of therapeutic strategies aimed at enhancing the secretion of beneficial cardiokines that minimize damage and maximize regeneration.